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rho kinase and mitochondria

So Young Kim, Sojung Park, SeonA Yoo, Jin Kyung Rho, Eun Sung Jun, Suhwan Chang, Kyung Kon Kim, Song Cheol Kim, Inki Kim
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential biological anticancer agent. However, a wide range of human primary cancers, including pancreatic cancer, display resistance to apoptosis induction by TRAIL. Therefore, this resistance needs to be overcome to allow TRAIL to be successfully used in cancer therapy. In this study, we performed a compound screen to isolate TRAIL sensitizers and found that one of the identified compounds, 7-benzylidenenaltrexone maleate (BNTX), sensitized pancreatic cancer cells to TRAIL-induced apoptotic cell death...
May 12, 2017: Oncotarget
S Balasubramaniam, L G Riley, D Bratkovic, D Ketteridge, N Manton, M J Cowley, V Gayevskiy, T Roscioli, M Mohamed, T Gardeitchik, E Morava, J Christodoulou
Clinical finding of cutis laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic cutis laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)-congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade...
April 13, 2017: Journal of Inherited Metabolic Disease
Jeremy P T Ward
Pulmonary hypertension is associated with oxidant stress and increased generation of reactive oxygen species (ROS) by NADPH oxidases (NOX), mitochondria and other sources. There is considerable evidence that these contribute to the aetiology via promotion of pulmonary vascular remodelling, endothelial dysfunction and enhanced vasoreactivity. However, it is now recognised that ROS act as important signalling mediators and second messengers under normal physiological conditions. Many ion channels and protein kinases critical to pulmonary vascular function are directly or indirectly affected by redox/ROS, including K(+) , Ca(2+) and nonselective cation channels and Rho kinase...
December 22, 2016: Experimental Physiology
Rafael Menezes da Costa, Rafael S Fais, Carlos R P Dechandt, Paulo Louzada-Junior, Luciane C Alberici, Núbia S Lobato, Rita C Tostes
Obesity is associated with structural and functional changes in the perivascular adipose tissue (PVAT), favoring the release of reactive oxygen species (ROS), vasoconstrictor and proinflammatory factors. Tumor necrosis factor alpha (TNF-α) induces vascular dysfunction and is produced by the PVAT. We tested the hypothesis that obesity-associated PVAT dysfunction is mediated by augmented mitochondrial ROS (mROS) generation due to increased TNF-α production in this tissue. Aortae from high fat diet (HFD)-fed obese mice displayed increased contractions to phenylephrine (PE) and loss of PVAT anticontractile effect...
December 8, 2016: British Journal of Pharmacology
Ming-Yu Liu, Jing Jin, Shan-Liang Li, Jie Yan, Chang-Lin Zhen, Jin-Lai Gao, Yong-Hui Zhang, Yan-Qiu Zhang, Xin Shen, Liang-Shuan Zhang, Yuan-Yuan Wei, Yu Zhao, Chen-Guang Wang, Yun-Long Bai, De-Li Dong
Mitochondria are dynamic organelles and continuously undergo fission and fusion processes. Mitochondrial fission is involved in multiple physiological or pathological processes, but the role of mitochondrial fission of smooth muscle cells in artery constriction is unknown. The role of mitochondrial fission of smooth muscle cells in arterial function was investigated by measuring the tension of rat mesenteric arteries and thoracic aorta and by evaluating mitochondrial fission, mitochondrial reactive oxygen species, and cytosolic [Ca(2+)]i in rat vascular smooth muscle cells...
November 2016: Hypertension
Su-Hua Huang, Jin-Cherng Lien, Chao-Jung Chen, Yu-Ching Liu, Ching-Ying Wang, Chia-Fong Ping, Yu-Fong Lin, An-Cheng Huang, Cheng-Wen Lin
Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, has five genotypes (I, II, III, IV, and V). JEV genotype I circulates widely in some Asian countries. However, current JEV vaccines based on genotype III strains show low neutralizing capacities against genotype I variants. In addition, JE has no specific treatment, except a few supportive treatments. Compound CW-33, an intermediate synthesized derivative of furoquinolines, was investigated for its antiviral activities against JEV in this study...
August 24, 2016: International Journal of Molecular Sciences
Sebastien Preau, Florian Delguste, Yichi Yu, Isabelle Remy-Jouet, Vincent Richard, Fabienne Saulnier, Eric Boulanger, Remi Neviere
AIMS: The RhoA/ROCK pathway controls crucial biological processes involved in cardiovascular pathophysiology, such as cytoskeleton dynamics, vascular smooth muscle contraction, and inflammation. In this work, we tested whether Rho kinase inhibition would beneficially impact cardiac cytoskeleton organization, bioenergetics, and autophagy in experimental endotoxemia induced by lipopolysaccharides (LPSs) in mice. RESULTS: Fasudil, a potent ROCK inhibitor, prevented LPS-induced cardiac inflammation, oxidative stress, cytoskeleton disarray, and mitochondrial injury...
April 1, 2016: Antioxidants & Redox Signaling
Xing-Zhen Sun, Shu-Yan Li, Xiang-Yang Tian, Qing-Quan Wu
OBJECTIVE: To investigate whether right ventricular hypertrophy in hypoxic pulmonary hypertension (HPH) rats could be prevented by treatment with Rho kinase inhibitor fasudil. METHODS: The rat model of pulmonary hypertension was established by exposing rats to normobaric intermitent hypoxia [(10 ± 0.5)% O2]. Twenty-four Spraque-Dawley male rats were randomly divided into control group, hypoxic model group and hypoxia with fasudil groups (n=8 each). The mean pulmonary arterial pressure (mPAP), and right ventricle hypertrophy index (RVHI) were measured...
2015: International Journal of Clinical and Experimental Pathology
Wei Shen, Lan Wang, Rongbiao Pi, Zhifeng Li, Rikang Wang
Paraquat (PQ) was demonstrated to induce dopaminergic neuron death and is used as a Parkinson's disease (PD) mimetic. Amounting evidences demonstrated that Rho/ROCK may a novel target for the therapy of PD. Previously we synthesized L-F001 and proved it is a potent ROCK inhibitor with multifunctional effects, including anti-oxidative stress. In this study, we investigated the effects and also the molecular mechanisms of L-F001 in preventing PQ-induced cytotoxicity in PC12 cells. L-F001 effectively prevented PQ-induced apoptotic cell death, which involves the scavenger of ROS and also attenuated the declined of mitochondrial membrane potential and intracellular level of GSH induced by PQ...
August 28, 2015: Biochemical and Biophysical Research Communications
Lamiaa A Ahmed, Hebatallah A Darwish, Rania M Abdelsalam, HebatAllah A Amin
3-Nitropropionic acid (3-NP)-induced neurotoxicity is an experimental model which mimics the pathology and motor abnormalities seen in Huntington's disease (HD) in human. The present investigation was directed to estimate the role of rho kinase (ROCK) inhibition in the possible protective effect of fasudil and simvastatin in 3-NP-induced striatal neurodegeneration in rats. Animals were injected s.c. with 3-NP (20 mg/kg/day) for 1 week with or without administration of fasudil (10 mg/kg/day, p.o.) or simvastatin (20 mg/kg/day, p...
August 2016: Molecular Neurobiology
Alban Ordureau, Jin-Mi Heo, David M Duda, Joao A Paulo, Jennifer L Olszewski, David Yanishevski, Jesse Rinehart, Brenda A Schulman, J Wade Harper
The PTEN-induced putative kinase protein 1 (PINK1) and ubiquitin (UB) ligase PARKIN direct damaged mitochondria for mitophagy. PINK1 promotes PARKIN recruitment to the mitochondrial outer membrane (MOM) for ubiquitylation of MOM proteins with canonical and noncanonical UB chains. PINK1 phosphorylates both Ser65 (S65) in the UB-like domain of PARKIN and the conserved Ser in UB itself, but the temporal sequence and relative importance of these events during PARKIN activation and mitochondria quality control remain poorly understood...
May 26, 2015: Proceedings of the National Academy of Sciences of the United States of America
Takafumi Miyamoto, Elmer Rho, Vedangi Sample, Hiroki Akano, Masaki Magari, Tasuku Ueno, Kirill Gorshkov, Melinda Chen, Hiroshi Tokumitsu, Jin Zhang, Takanari Inoue
AMP-activated protein kinase (AMPK), whose activity is a critical determinant of cell health, serves a fundamental role in integrating extracellular and intracellular nutrient information into signals that regulate various metabolic processes. Despite the importance of AMPK, its specific roles within the different intracellular spaces remain unresolved, largely due to the lack of real-time, organelle-specific AMPK activity probes. Here, we present a series of molecular tools that allows for the measurement of AMPK activity at the different subcellular localizations and that allows for the rapid induction of AMPK inhibition...
April 28, 2015: Cell Reports
Chenliang Zhang, Siyue Qin, Chang'an Jiang
PTEN-induced putative kinase 1 (PINK1), a Parkinson's disease (PD)-related protein, has two isoforms, the mitochondria-localized full-length isoform PINK1FL and the cytoplasm-localized short isoform PINK1-cyto. Studies have suggested that PINK1FL can selectively accumulate at the surface of damaged mitochondria and cooperate with another Parkinson's Disease-related protein PARKIN to trigger the degradation of MIRO1, a mitochondria trafficking regulator. The functions of PINK1-cyto are, however, not yet clear...
December 2014: Sheng Wu Yi Xue Gong Cheng Xue za Zhi, Journal of Biomedical Engineering, Shengwu Yixue Gongchengxue Zazhi
Yan Lei, Xiaoyong Peng, Liangming Liu, Zhaojun Dong, Tao Li
BACKGROUND: Vascular hyporeactivity plays an important role in severe trauma and shock. We investigated the beneficial effect of cyclosporine A (CsA) on traumatic shock and its relationship to vascular reactivity improvement and mitochondrial permeability transition pore (MPTP). MATERIALS AND METHODS: Sodium pentobarbital-anesthetized rats were used to induce traumatic hemorrhagic shock by left femur fracture and hemorrhage, the beneficial effects of CsA (1, 5, and 10 mg/kg, intravenously) on animal survival, cardiovascular function, tissue blood perfusion, and mitochondrial function of vital organs were observed...
May 15, 2015: Journal of Surgical Research
Rui Li, Xia Wang, Xiao-Hong Zhang, Hong-Hai Chen, Yan-Dong Liu
Ursolic acid, extracted from the traditional Chinese medicine bearberry, can induce apoptosis of gastric cancer cells. However, its pro-apoptotic mechanism still needs further investigation. More and more evidence demonstrates that mitochondrial translocation of cofilin-1 appears necessary for the regulation of apoptosis. Here, we report that ursolic acid (UA) potently induces the apoptosis of gastric cancer SGC-7901 cells. Further mechanistic studies revealed that the ROCK1/PTEN signaling pathway plays a critical role in UA-mediated mitochondrial translocation of cofilin-1 and apoptosis...
2014: Asian Pacific Journal of Cancer Prevention: APJCP
Ana B García-Redondo, Ana M Briones, Sonia Martínez-Revelles, Teresa Palao, Luis Vila, María J Alonso, Mercedes Salaices
AIM: : The aim of this study was to analyse the signalling pathways involved in H2O2 vascular responses in hypertension. METHODS: Vascular function, thromboxane A2 (TXA2) production, oxidative stress and protein expression were determined in mesenteric resistance arteries (MRAs) from hypertensive (spontaneously hypertensive rats, SHR) and normotensive Wistar Kyoto (WKY) rats. RESULTS: H2O2 and the TP agonist U46619 induced greater contractile responses in MRA from SHR than WKY...
January 2015: Journal of Hypertension
Jennifer L Larson-Casey, Shubha Murthy, Alan J Ryan, A Brent Carter
Protein kinase B (Akt) is a key effector of multiple cellular processes, including cell survival. Akt, a serine/threonine kinase, is known to increase cell survival by regulation of the intrinsic pathway for apoptosis. In this study, we found that Akt modulated the mevalonate pathway, which is also linked to cell survival, by increasing Rho GTPase activation. Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser(96). This phosphorylation in macrophages increased activation of Rac1, which enhanced macrophage survival because mutation of MDD (MDDS96A) induced apoptosis...
December 26, 2014: Journal of Biological Chemistry
Pei-I Tsai, Meredith M Course, Jonathan R Lovas, Chung-Han Hsieh, Milos Babic, Konrad E Zinsmaier, Xinnan Wang
Mutations in the mitochondrial Ser/Thr kinase PINK1 cause Parkinson's disease. One of the substrates of PINK1 is the outer mitochondrial membrane protein Miro, which regulates mitochondrial transport. In this study, we uncovered novel physiological functions of PINK1-mediated phosphorylation of Miro, using Drosophila as a model. We replaced endogenous Drosophila Miro (DMiro) with transgenically expressed wildtype, or mutant DMiro predicted to resist PINK1-mediated phosphorylation. We found that the expression of phospho-resistant DMiro in a DMiro null mutant background phenocopied a subset of phenotypes of PINK1 null...
2014: Scientific Reports
Ke He, Li Yan, Chun-Shui Pan, Yu-Ying Liu, Yuan-Chen Cui, Bai-He Hu, Xin Chang, Quan Li, Kai Sun, Xiao-Wei Mao, Jing-Yu Fan, Jing-Yan Han
Cardiac ischemia-reperfusion (I/R) injury remains a challenge for clinicians, which initiates with energy metabolism disorder. The present study was designed to investigate the protective effect of notoginsenoside R1 (NR1) on I/R-induced cardiac injury and underlying mechanism. Male Sprague-Dawley rats were subjected to 30-min occlusion of the left coronary anterior descending artery followed by reperfusion with or without NR1 pretreatment (5 mg·kg(-1)·h(-1)). In vitro, H9c2 cells were cultured under oxygen and glucose deprivation/reoxygenation conditions after NR1 (0...
December 15, 2014: American Journal of Physiology. Heart and Circulatory Physiology
Sara Travaglione, Stefano Loizzo, Teresa Rizza, Antonella Del Brocco, Giulia Ballan, Marco Guidotti, Rosa Vona, Michela Di Nottia, Alessandra Torraco, Rosalba Carrozzo, Carla Fiorentini, Alessia Fabbri
Mitochondria are dynamic organelles that constantly change shape and structure in response to different stimuli and metabolic demands of the cell. The Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1) has recently been reported to influence mitochondrial activity in a mouse model of Rett syndrome and to increase ATP content in the brain tissue of an Alzheimer's disease mouse model. In the present work, the ability of CNF1 to influence mitochondrial activity was investigated in IEC-6 normal intestinal crypt cells...
August 2014: FEBS Journal
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